chr21-45989119-GGGAGAAGCC-G

Position:

• chr21-45989119-GGGAGAAGCC-G

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1 PM2 PM4 PP3 PP5

The NM_001848.3(COL6A1):​c.846_854del​(p.Glu282_Gly284del) variant causes a inframe deletion change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency: Genomes: not found (cov: 33)
• Consequence: COL6A1 NM_001848.3 inframe_deletion
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1
• Conservation: PhyloP100: 8.56

Genes affected

COL6A1 (HGNC:2211): (collagen type VI alpha 1 chain) The collagens are a superfamily of proteins that play a role in maintaining the integrity of various tissues. Collagens are extracellular matrix proteins and have a triple-helical domain as their common structural element. Collagen VI is a major structural component of microfibrils. The basic structural unit of collagen VI is a heterotrimer of the alpha1(VI), alpha2(VI), and alpha3(VI) chains. The alpha2(VI) and alpha3(VI) chains are encoded by the COL6A2 and COL6A3 genes, respectively. The protein encoded by this gene is the alpha 1 subunit of type VI collagen (alpha1(VI) chain). Mutations in the genes that code for the collagen VI subunits result in the autosomal dominant disorder, Bethlem myopathy. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 3 uncertain in NM_001848.3
• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in NM_001848.3.
• PP3: No computational evidence supports a deleterious effect, but strongly conserved according to phyloP
• PP5: Variant 21-45989119-GGGAGAAGCC-G is Pathogenic according to our data. Variant chr21-45989119-GGGAGAAGCC-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 476440.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL6A1	NM_001848.3	c.846_854del	p.Glu282_Gly284del	inframe_deletion	9/35	ENST00000361866.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL6A1	ENST00000361866.8	c.846_854del	p.Glu282_Gly284del	inframe_deletion	9/35	1	NM_001848.3	P1

Frequencies

GnomAD3 genomes Cov.: 33

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 33

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Bethlem myopathy 1A Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Invitae

Jul 19, 2022

In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant disrupts the triple helix domain of COL6A1. Glycine residues within the Gly-Xaa-Yaa repeats of the triple helix domain are required for the structure and stability of fibrillar collagens (PMID: 7695699, 8218237, 19344236). In COL6A1, variants at these glycine residues are significantly enriched in individuals with autosomal dominant disease (PMID: 15689448, 24038877) compared to the general population (ExAC). ClinVar contains an entry for this variant (Variation ID: 476440). This variant has not been reported in the literature in individuals affected with COL6A1-related conditions. This variant is not present in population databases (gnomAD no frequency). This variant, c.846_854del, results in the deletion of 3 amino acid(s) of the COL6A1 protein (p.Glu282_Gly284del), but otherwise preserves the integrity of the reading frame. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Dec 21, 2016

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1556425474; hg19: chr21-47409033;